Project Summary The objective of this application is to leverage the infrastructure of the NINDS-funded multicenter, randomized, placebo-controlled Phase III HEAL (High-Dose Erythropoietin for Asphyxia and Encephalopathy) clinical trial of erythropoietin (Epo) vs. placebo for neuroprotection in neonates with moderate/severe hypoxic-ischemic encephalopathy (HIE) who also receive therapeutic hypothermia to determine the effect of Epo on important continuous, video electroencephalogram (cEEG) measures. The proposed ?HEAL-EEG? sub-study of the parent HEAL trial will test the central hypotheses that neonates who receive Epo will have a lower burden of neonatal seizures, and that cEEG background abnormalities and seizure burden will be associated with developmental disability at 2 years in both the placebo and Epo groups. We will test our hypotheses by pursuing two specific aims: 1) To determine whether neonates who receive Epo have a lower seizure burden than those who receive placebo and to assess whether lower seizure burden is associated with lower risk of adverse neurodevelopmental outcome and epilepsy, 2a) To determine whether neonates who receive Epo have altered cEEG background and to assess the ability of cEEG to predict adverse developmental outcome in neonates who receive Epo as compared to those who receive hypothermia alone, and 2b) To determine whether there is incremental added accuracy in predicting neurodevelopmental outcome at 2 years when adding cEEG seizure burden and background to clinical examination and MRI injury score. cEEG from 150 subjects enrolled in HEAL will be analyzed by two neurophysiologists with expertise in neonatal EEG for seizures and background patterns to compare seizure burden in Epo and placebo groups, as well as to examine the relationship between cEEG background pattern at six specified time points and neurodevelopmental outcome using Bayley Scales of Infant and Toddler Development, 3rd edition at 2 years. Upon successful completion of the proposed research, we expect our contribution to be a detailed understanding of how Epo affects seizure burden in neonates with HIE, as well as the predictive value of EEG in neonates undergoing hypothermia with and without Epo. The approach is innovative because it leverages the prospective randomized, controlled HEAL trial to evaluate critical cEEG measures in a way that cannot be accomplished in longitudinal cohort studies. HEAL-EEG will be the largest study to carefully evaluate detailed cEEG measures in a multicenter setting of a novel neuroprotective agent. The research is significant because it will add to our understanding of Epo?s mechanism of action, as well as inform clinicians in the rational utilization of cEEG in neonates with HIE by defining the risk and timing of seizures, as well as the prognostic utility of cEEG at various time points during and after hypothermia. Using tools like cEEG to predict neurodevelopmental outcome for neonates with HIE at the earliest possible time point is critical for clinical decision-making and parent communication.